The overall goal of our research is to identify the underlying cellular mechanisms of hair cell (HC) and spiral ganglia neuron (SGN) regeneration and synapse formation. HCs and SGNs can be lost from the effects of ototoxic drugs, aging and/or genetic dysfunction. We aim to determine whether inner ear HCs and SGNs can be replaced after such loss. We also seek to understand the regenerative process of the inner ear and to identify proliferative cell types in the brain with properties similar to HCs and SGNs. The specific aims of the study are to: 1) Identify adult stem cell (SC) types that have the potential to undergo functional switch or differentiation to assume the functions of HCs and SGNs using biochemical, molecular biology and biophysical strategies. 2) Determine the cellular mechanisms of HC-SGN synapse formation during regeneration using electrophysiological and biochemical indexes. 3) Identify the functional and cellular chain of events in the assemblage of transduction and electrical conductances for functional HCs and SGNs. 4) Promote the integration/innervations of HCs in the sensory epithelia by SGNs/SCs using electric fields (EFs) and to determine the underlying cellular mechanisms of SC integration. 5) Finally, improve hearing in a deafened animal model by engrafting SCs in the inner ear. These studies transcend inner ear-specific functions and regeneration. Since the mechanisms used by the inner ear may be expressed in different forms by other signal transduction systems, these studies may provide novel insights into SC differentiation, signaling and integration in the nervous system. We have collected convincing pilot data to show the feasibility of these studies. Thus, the study may represent a paradigm shift, and serve as a dry run for future therapy. PUBLIC HEALTH RELEVANCE: Hair cells (HCs) are terminally-differentiated cells and convert sound and balance signals into electrical impulses in the inner ear, with remarkable precision and sensitivity. Once HCs are lost due to noise, ototoxic drugs or aging, there is no effective way to stimulate their regeneration in mature inner ears. Our long-term goal is to stimulate HCs and/or identify adult stem cells capable of re-populating the mammalian inner ear and to enable the functional innervations of HCs by neurons.